title: Impact of manganese neurotoxicity on MMP-9 production and superoxide dismutase activity in rat primary astrocytes. Effect of resveratrol and therapeutical implications for the treatment of CNS diseases.
abstract: Manganese (Mn) is an environmental contaminant and its overexposure contributes to the pathophysiological processes of numerous disorders of the central nervous system in humans with mechanisms of action not completely understood. Activation of astrocytes and the subsequent release of neurotoxic factors have been implicated to contribute to neurodegeneration. Here, we assessed the molecular basis of the effects of Mn on modulation of matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) in rat astrocyte cultures. Primary cultures of rat astrocytes were exposed to different doses of MnCl2. Culture supernatants and cell lysates were used for the detection of MMP-2 and MMP-9 levels and mRNA expression, respectively. The exposure of astrocytes to MnCl2 induced the levels and expression of MMP-9 in a dose-dependent manner. The addition of resveratrol (RSV) inhibited both levels and expression of MMP-9 in astrocytes, whereas N-acetylcysteine (NAC) and quercetin (QRC) were ineffective in inhibiting MMP-9. As a possible mechanism of Mn-induced MMP-9, we determined intracellular redox state in Mn-treated astrocytes by assessing superoxide dismutase (SOD) activity and intracellular reactive oxygen species (ROS) and found a significant increase of ROS and a decrease of SOD activity. RSV, NAC, and QRC restored the redox state. The study of the mitogen-activated protein kinase signaling pathway demonstrated that MMP-9 transcription is mainly regulated by extracellular-regulated protein kinases (ERK). Pretreatment with RSV significantly reduced ERK activation suggesting that its ability to counteract MMP-9 overexpression is due not only to a general redox balance phenomenon but also to the modulation of ERK signaling pathway.
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Latronico
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Branà
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Merra
authors.forename: Anna
authors.initials: A
authors.lastname: Fasano
authors.forename: Gaetano
authors.initials: G
authors.lastname: Di Bari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Casalino
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Liuzzi
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008345:Manganese / Q000633:toxicity*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000096:biosynthesis*; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D013267:Stilbenes; D008345:Manganese; D011794:Quercetin; D013482:Superoxide Dismutase; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; D000077185:Resveratrol; D000111:Acetylcysteine
keywords: MAPK.; MMP; SOD; astrocytes; manganese; neurotoxicity